Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

Vivek Thumbigere-Math, Brian L. Foster, Mahesh Bachu, Hiroaki Yoshii, Stephen R. Brooks, Alyssa Coulter, Michael B. Chavez, Sumihito Togi, Anthony L. Neely, Zuoming Deng, Kim Mansky, Keiko Ozato, Martha J. Somerman

Research output: Contribution to journalArticle

Abstract

This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8G388S) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8WT control. Further, similar to subjects with heterozygous IRF8G388S mutation, Irf8+/– mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8–/– and Irf8+/– mice when compared with Irf8+/+ controls. Genomewide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease.

Original languageEnglish (US)
Pages (from-to)1155-1168
Number of pages14
JournalJournal of Bone and Mineral Research
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Tooth Resorption
Root Resorption
Tooth Root
Osteoclasts
Mutation
Periodontal Diseases
Nucleic Acid Regulatory Sequences
Osteogenesis
Transcriptional Activation
Genes
Tooth
Immunohistochemistry
Bone and Bones

Keywords

  • DENTAL BIOLOGY
  • EPIGENETICS
  • OSTEOCLASTS
  • OSTEOIMMUNOLOGY
  • OSTEOPOROSIS

Cite this

Thumbigere-Math, V., Foster, B. L., Bachu, M., Yoshii, H., Brooks, S. R., Coulter, A., ... Somerman, M. J. (2019). Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption. Journal of Bone and Mineral Research, 34(6), 1155-1168. https://doi.org/10.1002/jbmr.3690

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption. / Thumbigere-Math, Vivek; Foster, Brian L.; Bachu, Mahesh; Yoshii, Hiroaki; Brooks, Stephen R.; Coulter, Alyssa; Chavez, Michael B.; Togi, Sumihito; Neely, Anthony L.; Deng, Zuoming; Mansky, Kim; Ozato, Keiko; Somerman, Martha J.

In: Journal of Bone and Mineral Research, Vol. 34, No. 6, 01.06.2019, p. 1155-1168.

Research output: Contribution to journalArticle

Thumbigere-Math, V, Foster, BL, Bachu, M, Yoshii, H, Brooks, SR, Coulter, A, Chavez, MB, Togi, S, Neely, AL, Deng, Z, Mansky, K, Ozato, K & Somerman, MJ 2019, 'Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption', Journal of Bone and Mineral Research, vol. 34, no. 6, pp. 1155-1168. https://doi.org/10.1002/jbmr.3690
Thumbigere-Math, Vivek ; Foster, Brian L. ; Bachu, Mahesh ; Yoshii, Hiroaki ; Brooks, Stephen R. ; Coulter, Alyssa ; Chavez, Michael B. ; Togi, Sumihito ; Neely, Anthony L. ; Deng, Zuoming ; Mansky, Kim ; Ozato, Keiko ; Somerman, Martha J. / Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption. In: Journal of Bone and Mineral Research. 2019 ; Vol. 34, No. 6. pp. 1155-1168.
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abstract = "This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8G388S) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8WT control. Further, similar to subjects with heterozygous IRF8G388S mutation, Irf8+/– mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8–/– and Irf8+/– mice when compared with Irf8+/+ controls. Genomewide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease.",
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AU - Foster, Brian L.

AU - Bachu, Mahesh

AU - Yoshii, Hiroaki

AU - Brooks, Stephen R.

AU - Coulter, Alyssa

AU - Chavez, Michael B.

AU - Togi, Sumihito

AU - Neely, Anthony L.

AU - Deng, Zuoming

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AU - Ozato, Keiko

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